Through the adaptation of two murine skin tumor models, the studies proposed here will evluate the structure and function of cell surface-associated glycosaminoglycans in tumor progression. The long-term objective is to test the hypothesis that glycosaminoglycans function in tumor growth, and that this funciton is reflected by a correlation between the structure of certain of these substances and the tumorigenic potential of neoplasms.
The specific aims are: 1. To relate the growth rates of chemical- and ultraviolet radiation-induced tumor cell populations in vitro to cellular glycosaminoglycan content and to differences in the distribution of these substances within several compartmental pools associated with the cell and the extracellular matrix. To correlate molecular structure of the specific glycosaminoglycan, heparan sulfate, with the tumorigenicity phenotype of established tumor cell lines. Experimental protocols to manipulate the tumorigenic potential of the lines will be utilized in order to compare heparan sulfate structure between tumor cells which are progeny of the same, as well as of separate, transformation events. 3. To investigate the possible functional significance of phenotype-dependent differences in cellular heparan sulfate content in cell adhesive responses to tissue substrates. The involvement of the cell surface-associated material from tumor cell lines varying in tumorigenic potential will be detemrined by competitive ligand studies utilizing specific exogenous glycosaminoglycans and proteoglycans, and by the use of several heparan sulfate-degrading enzymes of well determined specificities. The cutaneous carcinogenesis models will provide a rigorous test of the hypothesis that tumorigenic phenotype correlates with cellular content of heparan sulfate, and they furthermore will enable an elucidation of the funcitonal significance of variations in the cell surface content of this specific glycosaminoglycan in cell-substrate adhesion.
